Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease, with a prevalence of 1% worldwide. Nearly two-thirds of RA patients suffer from loss of skeletal muscle mass, which often co-occurs with central obesity, a feature of metabolic syndrome [2]. Lower muscle mass leads to muscle weakness, a major contributor of physical impairment in patients with RA, even after multivariate adjustment for demographic and disease variables. My broad long-range goal is to understand at a mechanistic level the metabolic and physiologic abnormalities of skeletal muscle in patients with RA; and to use that knowledge to improve therapy for skeletal muscle dysfunction in RA. As a first step to achieve that goal, I hypothesize that increased lipid content in skeletal muscle contributes to insulin resistance and impaired skeletal muscle homeostasis and function in RA. I further hypothesize that treatment with pioglitazone will improve muscle function by decreasing lipid deposition in skeletal muscle, restoring the anabolic effects of insulin and attenuating inflammation. In order to test these hypotheses, I will establish a cohort of well-characterized RA subjects and non-RA controls, who will undergo assessment of physical function, body composition, disease activity, and needle biopsy from the vastus lateralis muscle (aim 1). In aim 2, I will conduct a 12-week, double-blind, and placebo- controlled study with pioglitazone in patients with RA who are insulin resistant to determine whether treatment of insulin resistance will improve functional characteristics, cellular and molecular responses in their skeletal muscle. Completion of the proposed research will begin to define the molecular underpinnings of impaired skeletal muscle homeostasis in RA. I will use the information gained from this cohort to design clinical interventions in this patient population to prevent and/or treat skeletal muscle dysfunction in RA. Ultimately, this work promises to provide novel targets to treat and prevent a devastating complication of RA.